Cycads have been a source of food and medicine for
many people who live in proximity to these plants. These plants are well-known
to be highly poisonous and must be carefully processed to remove toxins, before
they are edible. If they are not properly processed they can cause vomiting, liver
damage and even death, there is also evidence they have neurotoxic effects. To
remove the toxins, different methods of processing are
used by different cultures.

Cycad Poisoning

Cycad poisoning in sheep causes two distinct syndromes which appear to
be mutually exclusive. Either gastrointestinal disturbances with liver damage
is seen, or else paralysis of the hind limbs and death due to starvation. In
Australia, this paralysis is known as 'zamia staggers' and results from cattle
grazing on cycad leaves
(Hall & McGavin 1968).
In the affected animals nerve cell death is seen in the spinal cord.

This syndrome has not been observed in wild animals which eat cycads.

Cycads and Guam Dementia

For more than 50 years, it has been noticed that the Chamorro people
who live on the West Pacific Island of Guam have a very high incidence
of a fatal, paralyzing, neurodegenerative disease. Amyotrophic lateral sclerosis
(ALS) and parkinsonism-dementia (PD) was found to be up to 100 times more
common in Guam than in the US and other developed countries
(Garruto 1980).
The disease has a wide spectrum of symptoms ranging from ALS muscle degeneration
and weakening to parkinson-like tremor and catatonia as well as dementia.
The disease has a late onset and generally appears between the ages of 25-40
years old. One of the pathological features of the Guamian ALS-PD include
neurofibrillary tangles, which are found in damaged nerve cells
(Hirano 1961,
Hirano & Zimmerman 1962).
and are a hallmark of many neurodegenerative diseases, such as Alzheimers.
A loss of sense of smell is also characteristic, as in Alzheimers
(Doty et al. 1991).

Despite years of intensive research, the cause of the disease remains a mystery.
Although it is restricted to certain areas and families, no genetic link has been
made and the disease does not follow Mendelian ratios. Neither has an infectious
agent been found. Could ALS-PD be caused by some neurotoxin in the Chamorro
people's environment ?

In India a similar neurodegenerative disease called Lathyrism, had been
conclusively linked to consumption of the grass-pea (Lathyrus sativus,
L. cicera, & L. clymenum), which was found to contain
the neurotoxin beta-N-oxalylamino-L-alanine
(BOAA).
Lathyrism causes
fatal motoneurone wasting similar to ALS
(read the
Lathyrus Lathyrism Newsletter).
Could both diseases have a similar
cause? In 1963, the anthropologist Marjorie Whiting made an in depth investigation
into the use and preparation of the cycads in Guam , and she concluded that consumption
and medicinal use of cycads must be linked to the disease
(Whiting 1963).

Are Cycads Related to ALS-PD?

Similar symptoms to the Guamian disease have been found in two other areas
where species of Cycas are known to grow; the West of New Guinea and
the Kii Peninsula of Japan. Could use of cycads lead to developing ALS-PD in
later life? Since the causal link was made in 1963, the search has been on to find
concrete evidence for this hypothesis and to isolate the substances involved.

The people of Guam depended heavily on flour made from the starch extracted
from cycad seeds, particularly when there were food shortages during and after World
War II. Epidemiology has shown a subsequent increase in ALS-PD in the years following
this. As well as eating the cycad starch, the Chamorros used the raw seeds to make
poultices for wounds. Was this exposing the Chamorros to some neurotoxin within the cycads?

Substances Involved in Cycad Toxicity

Like most plants, Cycads contain characteristic chemicals, which are unique to
their order of plants.

As popularity for the BMAA hypothesis wanes, new evidence has led to another
look at cycasin's role in the disease. The botanist Knut Nortstog observed that
Cycas (the genus found in Guam) produce large quantities of pollen. This
pollen is heavily laden with cycasin and BMAA. Carried in pollen this cycasin or
other toxins (e.g., BMAA) could reach the brain by transfer through the olfactory
epithelium in the nose. The enzyme p450 which produces the toxic intermediate from
MAM in the liver is also found in the nose. In mice given MAM intranasally, damage
was seen in the olfactory epithelium. It is likely that damage in this area would facilitate
uptake of toxins into the brain
(Seawright et al. 1995).
This idea provides a new route for cycad toxins to enter the body and suggests the
possibility of a cumulative effect. After years of living in proximity to fertile cycads,
chronic exposure to pollen could provide high enough levels of toxin.

Another suspect in the etiology of the disease is zinc, which is known to be toxic to neurons
(Duncan et al. 1992).
They found that zinc was leached from the galvanized metal buckets used to wash
and process the cycad material. The longer the cycads were left in the bucket the higher
the zinc concentration of the resulting flour. Analysis of guamian cycad flour found it to
contain high concentrations of zinc. However, galvanized zinc buckets have not always
been used and although this hypothesis works in the lab, it is not likely to explain the
problems in Guam.

Questions Remaining and Implications

1. Why does the disease only appear later in life?

A theory has been put forward for 'slow acting' neurotoxins
(Spencer et al. 1987).
The effects of BMAA or some other toxin could be cumulative over many years.
Alternatively, the toxins could cause subclinical amounts of damage, which only
becomes apparent in later life when neuronal numbers start to decrease naturally.

2. Could there be some interaction between MAM / BMAA or one of the products of their metabolism in vivo?

The toxicity of cycads could come from MAM facilitating the neurotoxic activity of BMAA.

Isolating the cause of ALS-PD of Guam could help to elucidate the mechanism of nerve
cell damage and death. If etiology is due to an environmental toxin there are interesting
implications for other neurodegenerative diseases, like Alzheimers.

Meanwhile a new role for BMAA as a signaling protein within plants has been found
(Brenner et al. in press ).
and not just as a defense against hervbivory. A recent experiment by Hon-Ming Lam et al.
(1998)
showed that some species of plants have receptors glutamate which are very similar to
the glutamate receptors present in animal brains. With BMAAs structural similarity to
glutamate it may be used in plants for cell to cell communication, in the same way glutamate
is used for cell to cell signaling in the brain.